Catechol thiazoles and process of making the same



Patented Jan. 7, 1930 UNITED STATES PATENT OFFICE TREAT B.

' A COMPANY, or nnw'yonx,

JOHNSON, on nn rnnnmconnnc'rrcur, essienon 'ro wrnrnnor cumulon- A CORPORATION OF NEW YORK CATECHOL AND PROCESS OF MAKING THE SAME No Drawing.

The present invention relates to catechol thiazole compounds, and residesin thiazole compounds containing in position ---4: of the thiazole ring, and to processes of preparing the same.

5 I have discovered that new thiazole compounds corresponding to the general formula.

HO HCS 5 1 4 2 HO V .X

wherein X represents one of the groups, amino, alkylamino, dialkylamino, aminoalkyl, alkyLaminoalkyl, dialkyl-aminoalkyl, acetylaminoalkyl, acetylalkylamino, mercapto, aryl, alkylaminohydroxya 'kyl and alkoxyl, may be synthesized and that the said new compounds bear a close therapeutic similarity to the known compounds of the type formula I H KOO-0.x where X has the values above expressed.

One procedure which is susceptible to general application in the synthesis of the new compounds of the genus above defined con- Application filed February a,

the catechol nucleus 1928. Serial No. 251,742.

tution whichinay be representedby the general formula' I .x N?

wherein Y represents one of the elements of I the group sulfur and selenium,'and X represents one of the groups amino-, alkylamino-, dialkylamino-, aminoalkyl-, alkylaminoalkyl-, dialkyl'aminoalkyL, acetylaminoalkyl-, acetylalkylamino-, mercapto-, aryl-, alkylamino hy droxy alkyl-, and alkoxyl. While the equivalency of selenium and sulfur in the aforesaid grouping are, for example thioamides, thioureas, thio carbamates and dithiocarbamates. The reaction, which may be expressed graphically by the equation HO no--s sists in condensing a halogenacetopyrocate" chol,-preferably, chloroacetopyrocatechol with an organic compound containing either sulfur orselenium and a trivalent nitrogen atcm both attached to a single carbon 5 atom, said organic compound having a constigenerally may be efi'ected bybringing together chloroacetopyrocatechol and one of the above described reactants in solution in a mutual solvent, such as, for example, an alcohol such as ethyl alcohol, an ether, an acetonelike solvents or the like, but preferably, ethyl alcohol, and suitably heating the solution mixture. The resulting thiazole compounds usually are separated 4 from the solvent, by cooling, in the form of their hydrochlorides, or of their free bases, having definite crystalline structure. The reaction elfects a bridging,by means of a thiazole ring,or the aromatic nucleus and side chains of compounds of the type of adrenaline:

ha thiazole H. .OH 7 m and ephedrine:

I'HI

6a. A feature of especial interest from the standpoint of therapy is that the said thiazole-containing compounds possess substantially the same physiological efiicacy as do the corresponding catechol-containing compounds not containing the thiazole ring bridge, differing from the latter only in that the bridged compounds exhibit a markedly diminished toxicity.

The following examples serve to describe the invention more fully.

Ewample I.Preparation of 2-amino-4- (3,4) dihydroxyphenyl-thiazole hydrochloride.

' 5 parts by weight of thiourea and 12 parts by weight of chloroacetopyrocatcchol are dissolved m from 5 to 7 parts by weight of ethyl alcohol and the solution heated on a Water bath at a temperature of 100 C. for a period of from one-half to one hour. cooling the solution after completion of the reaction, 2-amino-4(3,4) dihydroxy-phenylthiazole, having most probably the H0 HOE-S HOOQ\N%JLNHI in the form of its hydrochloride,separates out in the form of colorless crystals. Dilution of the alcohol with acetone expedites the separation step. The yield is approximately 2.5 to 2.8 times the thiourea employed. From the compound soluble salts chloride is easily purified by re-crystalliza- 7 tion from ethyl alcohol. It is soluble in Water and ethyl alcohol, and insoluble in ether, benzene, acetone, andethyl acetate. It decomposes at 230235 alysis: Calculated for C,H.N SCLH5O:C=41.1; H=4.2;

formula weight of the Example [Ir-Preparation of Q-methylamino-4(3,4) dihydroxyphenylthiazole hydro chloride. i

5 parts by weight of methylthiourea and 10 parts by weight of chloroaceto yrocatechol are dissolved in from 5 to? parts y weight of ethyl alcohol, and the solution iswarmed only gently (i.'e., up to about 506 0 (3.). An.im-' mediate reactlon obtains, and, after coolin formula HO tics noOlk aNHoH,

separates out in quantitative filtering and washing with acetone, the salt methylaminomethyl-4(3,4) dihydroxyphenyll thiazole hydrochloride.

6 parts by weight of acetylmethylaminoacetothioamide noxs is obtained corresponding to -90 percent of that theoretically obtainable. The salt is purified by dissolving in alcohol and precipitating with ether. It has a melting point of 186188 C. (Analysis: Calculated for ga ,,O N SCl:N=8.9. .Found:N, 8.85 and bj'wampl e [V.-Preparation of 2-methylanliinomethyl 4 (3,4) -dihydroxyphenyl thiazo e This 0 pound having most robably' the formula Gin p the hydrochloride of 2-methylamino 4(3,4)' 75 'dihydroxyphenyl thiazole of the probable yield. After use -, is readily formed by hydrolysis of its corresponding acetyl derivatives (i. e., the product of Example III). The hydrol sis is accomplished by digesting the acetyl derivative with strong hydrochloric acid in a boiling water bath; the change is complete after about 2 hours digestion. The vield of hydrochloride sa lt corresponds to about 80-85 percent of the theoretical. The salt is purified by dissolving in absolute alcohol and precipitating with ether. It decomposes at 220- 225 C. It is soluble in water and in alcohol. The free base melts at l28130 C. (Analysis: Calculated for C H O N S.C H OH:- N=9.93. Found: N, 99240.0.)

Example V.Preparation of 2-phenyl- 4 (3,4) -dihydroxyphenyl thiazole.

4 parts by weight of thiobenzamide and 5 parts by Weight of chloroacetopyrocatechol are dissolved in 10 to 12 parts of ethyl alcohol, and the solution is refluxed on a boiling water bath; the reaction is complete after 12 hours. Upon cooling the solution the free thiazole having the probable formula H0 V Ho---s cohol and melts at 164165 C. (Analysis:

Calculated for C H O NS.H O:'N=4.86. Found: N, 4.7; 4.6)

Example (3.4) -dihydroxyphenyl thiazole has the melting point 198200 C.

Example Vlfl'.2-aminoisopropyl-4 (3,4)

- 'dihydroxyphenyl thiazole in the form of its hydrochloride, is soluble in Water and in alcohol. It decomposes at 2l02l5 C.

Vl.-2 acetylaminomethyl 4- Example IX.2-aminomethyl-4 (3,4) -dihydroxyphenyl thiazole zero-s nob-ikydonmm is produced, in the form of its hydrochloride,

Ho Ho--s HOOE LSH This compound, obtainable by condensation of chloroaceto-pyrocatechol and ammonium dithiocarbamate is insoluble in Water and soluble in alcohol.

It melts at 250 C. with decomposition. The

sulfur is firmly bound, not being removed by treatment with alkali.

Example Xl.2- (a-hydroxy-B-methylamino) -ethyl 4 (3,4) dihydroxyphenylthiazole (thiazole adrenaline) This compound may be obtained by condenslng chloroacetopyrocatechol and a-hydroxy- ,B-methylamino-thiopropionamide.

momnomomon .o.s.NH,

the said thiazole compound also may be prepared by an indirect procedure involving the substitution of 'a methylamino group for chlorine in the compound 2-chloroacetyl-4- (3,4) -dihydroxyphenyl thiazole HO Hps HoOck dooomoi and reducing the resulting compound; thus:

I OH H cl tp a.

Example XII.-2- (a-hydroxy B methylamino) -propy1-4(3,4) -dihydroxypheny1 th1- azole (thiazole ephedrine):

- Ho PR on n l J HOOl l l g m (BH: The compound may be prepared by condensing chloroacetopyrocatechol and a-hydroxy- ,B-methylamino-thiobutryamide CH: i

v mcxnitnomomclaum or, by an indirect procedure,- according to 5 the following equation:

HaH

.g l a u L I a I L HOO \N%C.CHQOHI-fi R.C N .CHiCl+sodiumsa1tolmalonlcester n.ii .omonmrmooon B. Another illustration involves the oxidation of the alcohol to the corresponding aldehyde II and acid III on-s cH-'-s mk tcno and nik imoon n. In. Applying fundamental type reactionsto one or the other of these two simple combinations one obtains new thiazole'combinao5 tions containing more complex side chains. I

It is to be understood that, for the purposes of the present invention, the type groupings: 1

are considered to be isomeric representations of identical compounds. Likewise, as has been indicated hereinbefore, seleniumis to be understood as being the equivalent of sulfur in the above type groupings.

I claim: 1.- Process which comprises condensing with a halogen-acetopyrocatechol an organic compound containing the grouping with chloroacetopyrocatechol a compound of I the general formula wherein X represents a residue containing a trivalent nitrogen atom.

4. Process which comprises condensing with chloroacetopyrocatechol a compound of thegeneral formula m0 5. Process which comprises condensing with chloroacetopyrocatechol a compound of the general formula sn 7 1a wherein X represents one of the groups aminoalkylamino, di lamino, aminoalkyl, alkylaminoalkyl, di laminoalkyl, acetylalkylamino, acetylaminoalkyl, mercapto, aryl, alkylaminohydroxyalkyl and alkoxyl.

6. As new roducts, compounds of the general form a wherein X represents a residue containing a trlvalent nitrogen atom.

7. As new products, compounds of the general formula wherein X represents an aliphatic side chain containing a trivalent nitrogen atom.

8. As new roducts, compounds of the general form a Ho---s HO-C H L' wherein X represents one of the groups, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,

acetylalkylamino, acetylannnoalkyl, mercapto, aryl, alkylaminohydroxyalkyl and alkoxyl, being in the solid state, generally crystalline products of basic nature and soluble in ethyl alcohol and insoluble in ether,

benzene, acetone and ethylacetate.

In testimony whereof, I aflix m slilgnature.

TREAT B. JO SON. 

